Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine with osteoclastogenic and osteolytic activities that contribute to pathogenesis of bone disorders such as periodontal disease, post-menopausal osteoporosis, and arthritis. This proposal will investigate mechanisms underlying TNF-alpha stimulation of osteoclast formation from mouse bone marrow macrophages (BMM). Proposed studies are based on the premise that two TNF-alpha receptors transduce TNF-alpha signals in osteoclast precursors with opposing effects on osteoclast formation. The p55 receptor (p55r) is proposed to mediate positive effects of TNF-alpha (mainly soluble TNF-alpha) on osteoclast formation through activation of c-src kinase, subsequent phosphorylation and inactivation of the NFkB inhibitor IkBalpha, and activation of NFkB. The p75 receptor (p75r) is proposed to mediate inhibitory effects of TNF-alpha (mainly membrane TNF-alpha) on osteoclast formation. This hypothesis is supported by previous studies and preliminary data. The specific aims of the proposal are (1) to determine the mechanisms by which p55r promotes osteoclastogenesis, and (2) to determine the mechanisms by which p75r suppresses osteoclastogenesis.